6-1611567-GGGCGGCGGC-GGGC

Variant names:

• chr6-1611567-GGGCGGC-G
• rs76840944
• NM_001453.3:c.1136_1141delGCGGCG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BS1_Supporting BS2

The NM_001453.3(FOXC1):​c.1136_1141delGCGGCG​(p.Gly379_Gly380del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,142,748 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G379G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: FOXC1 NM_001453.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.46
• Publications: 6 publications found

Genes affected

FOXC1 (HGNC:3800): (forkhead box C1) This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding forkhead domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development. Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld-Rieger anomaly. [provided by RefSeq, Jul 2008]

FOXC1 Gene-Disease associations (from GenCC):

• anterior segment dysgenesis 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• Axenfeld-Rieger syndrome type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• aniridia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Axenfeld anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated aniridia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Peters anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Rieger anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001453.3
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000614 (9/146528) while in subpopulation SAS AF = 0.00104 (5/4794). AF 95% confidence interval is 0.00041. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXC1	NM_001453.3	c.1136_1141delGCGGCG	p.Gly379_Gly380del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000645831.2	NP_001444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXC1	ENST00000645831.2	c.1136_1141delGCGGCG	p.Gly379_Gly380del	disruptive_inframe_deletion	Exon 1 of 1		NM_001453.3	ENSP00000493906.1

Frequencies

GnomAD3 genomes AF: 0.0000615 AC: 9 AN: 146426 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000606

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000622 AC: 62 AN: 996220 Hom.: 1 AF XY: 0.0000672 AC XY: 32 AN XY: 475954

African (AFR) AF: 0.00 AC: 0 AN: 19812

American (AMR) AF: 0.00 AC: 0 AN: 5788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11264

East Asian (EAS) AF: 0.000360 AC: 4 AN: 11126

South Asian (SAS) AF: 0.000397 AC: 9 AN: 22672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2442

European-Non Finnish (NFE) AF: 0.0000517 AC: 45 AN: 871222

Other (OTH) AF: 0.000109 AC: 4 AN: 36792

GnomAD4 genome AF: 0.0000614 AC: 9 AN: 146528 Hom.: 0 Cov.: 24 AF XY: 0.0000841 AC XY: 6 AN XY: 71316

African (AFR) AF: 0.00 AC: 0 AN: 40870

American (AMR) AF: 0.00 AC: 0 AN: 14764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 4836

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000607 AC: 4 AN: 65952

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Axenfeld-Rieger syndrome type 3 Uncertain:2

Aug 21, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1136_1141del, results in the deletion of 2 amino acid(s) of the FOXC1 protein (p.Gly379_Gly380del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with FOXC1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed inframe deletion variant c.1136_1141del(p.Gly379_Gly380del) in the FOXC1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. This p.Gly379_Gly380del causes deletion of amino acid Glycine at position 379 to Glycine at position 380. This variant has been reported to the ClinVar database as Uncertain significance. This variant is predicted to cause changes in the protein length resulting from in-frame deletion. For these reasons, this variant has been classified as Uncertain significance. -

Axenfeld-Rieger syndrome type 3;C5975707:Anterior segment dysgenesis 3 Uncertain:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=193/7	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76840944; hg19: chr6-1611802;